This invention is directed to providing biocompatible biodegradable polymers or copolymers linked to a plurality of functional groups and the products resulting from reaction of some or each of the functional groups to attach moieties containing aminoxyl-containing radicals or comprising other drug molecule residues or other biologically active agent residues.
Aliphatic polyesters are a group of biomaterials that have commercially successful application because of their biodegradability and biocompatibility. Although these polymers have been used extensively as sutures, implant materials and drug carriers, they do not have any inherent biological functions to actively participate in human body repair.
Nitric oxide has become one of the most studied compounds in biochemistry and biology, and this compound and its biological functions are the subject of many reviews. However, excessive introduction of nitric oxide into the body may have adverse side effects such as microvascular leakage, tissue damage, septic shock, B-cell destruction and possible mutagenic risk. Therefore, it is important to control nitric oxide concentration and release.
Lee et al. U.S. Pat. No. 5,516,881 is directed to providing a nitric oxide-like stable free radical in the form of an aminoxyl-containing radical at the chain end of a polymer or copolymer including aliphatic polyester, as an approach to controlling nitric oxide concentration and release. The resulting product is limited in terms of the concentration of aminoxyl-containing radical available.
It has been discovered herein that biocompatible biodegradable polymers or copolymers allowing flexibility in available concentration of attached aminoxyl group or attached drug residue or attached biologically active agent residue is provided by providing a plurality of moieties containing aminoxyl-containing moiety or other drug molecule residue or other biologically active agent residue covalently or ionicly attached thereto.
One embodiment of the invention, denoted the first embodiment, is directed to a biocompatible biodegradable copolymer comprising a polymeric or copolymeric segment containing hydrolyzable ester or nitrogen-phosphorus linkage and which is capped at one end and linked at the other end to a polymeric or copolymeric segment having a plurality of functional groups pendant thereto, some or each of the functional groups being reacted to attach a moiety containing an aminoxyl-containing radical or to attach a moiety comprising other drug molecule residue or other biologically active agent residue.
Another embodiment of the invention, denoted the second embodiment, is directed to a biocompatible biodegradable polymer or copolymer which is capped at one end and has a free hydroxyl at the other end. The free hydroxyl can be reacted to attach moiety with unsaturation therein which in turn can be reacted to provide end segment with a plurality of functional groups thereon. Some or each of the functional groups can be reacted to attach a moiety containing an aminoxyl-containing radical or to attach a moiety comprising other drug molecule residue or other biologically active agent residue.
In still another embodiment herein, denoted the third embodiment, there is provided an admixture of biocompatible biodegradable polymer or copolymer which is capped at one end and contains at the other end a segment or segments with a plurality of functional groups thereon and a spin label and/or other drug molecule and/or other biologically active agent, e.g. in a weight ratio ranging from 1:99 to 99:1 polymer or copolymer to spin label, other drug molecule and other biologically active agent, to form a polymer drug matrix, for delivering the spin label, other drug and/or other biologically active agent, e.g. with controlled, e.g. sustained or delayed, release functionality.
In still another embodiment of the invention herein, denoted the fourth embodiment, there is provided a drug release system for biomedical application comprising the copolymer of the first embodiment or the admixture, polymer drug matrix, of the third embodiment.
In yet another embodiment of the invention herein, denoted the fifth embodiment, a stent is coated with the drug release system of the fourth embodiment to provide a drug eluting coating on the stent.
The term xe2x80x9cbiocompatiblexe2x80x9d is used herein to mean material that interacts with the body without undesirable aftereffects.
The term xe2x80x9cbiodegradablexe2x80x9d is used to mean capable of being broken down into innocuous products in the normal functioning of the human body, tissues and cells and living organisms (e.g., bacteria).
The term xe2x80x9caminoxylxe2x80x9d is used herein to refer to the structure  greater than Nxe2x80x94O.. The term xe2x80x9caminoxyl-containing radicalxe2x80x9d is used herein to refer to a radical that contains the structure  greater than Nxe2x80x94O..
The term xe2x80x9cmoiety comprising other drug molecule residuexe2x80x9d is used herein to refer to moiety comprising drug molecule minus any portion thereof separated on attachment to become part of the biocompatible biodegradable copolymer. The word xe2x80x9cotherxe2x80x9d means that the drug does not contain a group containing the aminoxyl structure. The term xe2x80x9cdrugxe2x80x9d is used herein to mean a substance for use in the diagnosis, cure, mitigation, treatment or prevention of disease.
The term xe2x80x9cother biologically active agentxe2x80x9d includes proteins, cytokines, oligonucleotides including antisense oligonucleotides, genes, carbohydrates and hormones, but excludes compounds containing an aminoxyl containing radical and xe2x80x9cother drug molecules.xe2x80x9d The term xe2x80x9cresiduexe2x80x9d is used to mean said agent minus any portion of the biologically active agent separated on attachment to become part of the biocompatible biodegradable polymer or copolymer.